Process for the manufacture of bipyridyls

ABSTRACT

A process for the manufacture of bipyridyls which comprises reacting the corresponding substituted pyridine with ammonia in the vapour phase, the substituted pyridine being a 2(pyridyl)tetrahydropyran or tetrahydrothiopyran, a 4(pyridyl)tetrahydropyran or tetrahydrothiopyran, or a substituted pyridine wherein the substituent is a group of the structural formula - C(R)(R1)(R2) wherein R represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group or an amino group, and R1 and R2 each represents a group of the general formula CHn(XR3)2 nCHm(XR4)3 m wherein X represents an atom of sulphur or oxygen, n is 0, 1 or 2 and m is 1 or 2, and R3 and R4 each represents a hydrogen atom or an alkyl, alkene, alkaryl, aralkyl or cyclo-aliphatic group.

United States Patent Bowden Mar. 25, 1975 PROCESS FOR THE MANUFACTURE OF [56] References Cited BIPYRIDYLS UNITED STATES PATENTS [75] Inventor: Roy Dennis Bowden, Runcorn. 3,306,905 2/1967 Hall et a1 260/290 P England 73 Assignee: Imperial Chemical Industries Primary Examiner-Alan L. Rotman Limited, London, England Attorney, Agent, or Firnz-Cushman, Darby & I Cushman [22] F1led: Nov. 2, 1973 1 1 pp 412,093 [57] ABSTRACT Related US. Application Data A process for the manufacture of bipyridyls which [60] Continuation of Ser. No. 174,175, Aug. 23, 1971, Comprises reacting? Corresponding Substituted P abandoned, which is a division of Ser. No. 804,993, dine with ammonia in the vapour P the Substi- March 6, 1969 Pat. No. 3,651,071. tuted pyridine being a 2-(pyridyl)tetrahydropyran or tetrahydrothiopyran, a 4-(pyridyl)tetrahydropyran or [30] Foreign Application Priority Data tetrahydrothiopyran, or a substituted pyridine wherein MM [8 1968 United Kingdom woos/68 the substituent is a group of the structural formula May 29. was United Kingdom 25773/68 00 2) wherein R represents H hydrogen Dec. 20,1968 United Kin dom 6(1714/68 mom, a ge atom, a hydroxy group, an alkyl Dec. 20 1968 United Kingdom 60715/68 group of 1m ammo group, and i and 2 each P DU 30 1968 United Kingdom 607mm}; sents a group of the general, formula -CH,,(XR Jan. 2. 1969 United Kingdom 246/69 2-ii M 0 -m wherein X represents 11mm of sulphur or oxygen, n is 0, l or 2 and m is l or 2, and 52 us. Cl 260/296 D 3 and 4 each represents a hydrogen atom or an 51 Int. Cl i. C07d 31/42 i alkehei y aralkyl 0r y ph p [58] Field of Search 260/296 D, 290 P 11 Claims, No Drawings PROCESS FOR THE MANUFACTURE OF .BIPYRIDYLS This is a continuation of application Ser. No. 174,175, filed Aug. 23, 1971, now abandoned, which is a division of Ser. No. 804,993, filed Mar. 6, 1969, now U.S. Pat. No. 3,651,071.

This invention relates to pyridine derivatives and their manufacture and particularly to novel substituted pyridines and processes for the manufacture of substituted pyridines, and to a process for the manufacture of bipyridyls from substituted pyridines.

According to the present invention we provide a process for the manufacture of bipyridyls which comprises reacting the corresponding substituted pyridine with ammonia in the vapour phase, the substituted pyridine being a 2-(pyridyl)-tetrahydropyran or tetrahydrothiopyran, or an unsubstituted 4-(pyridyl)-tetrahydropyran or -tetrahydrothiopyran or a substituted pyridine wherein the substituent is a group of the structure formula C(R)(R1)(R wherein R represents a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group or an amino group, and R, and R each represents a group of the general formula CH,,(XR ,,.CH,,,(XR wherein X represents an atom of oxygen or sulphur, n is 0, l or 2 andm is 1 or 2, and R and R each represents a hydrogen atom or an alkyl, alkene, aryl, alkaryl or cyclo-aliphatic group. In the pyridine derivatives (including the pyridyl tetrahydropyrans and tetrahydrothiopyrans), the substituent may be in the 2, 3 or 4 position in the pyridine nucleus.-

The reaction is preferably carried out in the presence of molecular oxygen.

The substituted pyridine starting material in the vapour phase is heated with ammonia advantageously at a temperature in excess of 250C, preferably 350-450C, for example about 380C, usually in the presence of catalyst. Suitable catalysts include alumina, silica, silica-alumina, magnesia, chromia and mixtures thereof; these catalysts may contain platinum and/or palladium (as the metal or its oxide) in finely-divided form. Particularly suitable catalysts are the dehydrogenation catalysts, e.g. nickel, cobalt, copper, chro' mium and copper chromite. Preferably the reaction mixture contains molecular oxygen as, for example, oxygen gas which can be conveniently added in the form of air, although any molecular oxygen containing gas may be used.

The starting material can be vaporised simply by heating it to the required temperature and a particularly suitable technique is to drop the material in a stream of droplets onto a hot surface, for example onto a vaporiser or onto the catalyst for the reaction with ammonia. The material can be conveniently vaporised in a vaporiser prior to contact with the catalyst. Some of the starting materials are, however, tacky, viscous liquids or solids at ordinary temperatures and these are conveniently dissolved in a suitable solvent prior to vaporisation. Examples of suitable solvents for this purpose are water and alcohols, especially lower aliphatic alcohols and particularly methanol. I

The bipyridyls produced by the processcan be isolated from the reaction products by known techniques. For example, the gaseous reaction products can be condensed and the bipyridyl can then be isolated from the condensate by solvent extraction and/or fractional distillation, if desired under reduced pressure. If water is present in the reaction product obtained in the production of 4,4'-bipyridyls, these bipyridyls can be separated by filtration.

The process, whether a single or two-stage process, can be carried out batch-wise but has the advantage that it can be carried out as a continuous operation.

The process is particularly suitable for the production of 4,4'-bipyridyls although other isomers. for example 2,2-, 2,4'-, 2,3- and 3,4'- bipyridyls can be obtained by suitable choice of the starting material.

In addition to the compounds mentioned hereinbefore which can be reacted in the vapour phase with ammonia and oxygen to produce bipyridyls, there are a further class of substituted pyridines which can be converted to bipyridyls by the same reaction. These are substituted pyridines wherein the substituent contains a nitrogen atom and is a piperidyl group or a group of structural formula C(R)(R )(R wherein R is, and one of R and R may be, as hereinbefore defined but wherein at least one of the groups R, and R has the general formula CH .CN, CH2.CON(R5)(R6) or CH .CH N(R )(R,,) wherein R R R and R each represents a hydrogen atom or an alkyl, alkene, aryl, alkaryl, aralkyl or cyclic-aliphatic group. In this case, however, the presence of ammonia is not essential although it is beneficial.

According to the present invention therefore, we also provide a process for the manufacture of bipyridyls which comprises oxidising the corresponding substituted pyridine with molecular oxygen in the vapour phase, the substituted pyridine having a substituent which is a piperidyl group or a group of the formula -C(R)(R,,)(R where R is as hereinbefore defined, R represents a group of the general formula CH .CH, -Cl-l .CON(R )(R or CH .'CH N(R )(R,,) as defined in the immediately preceding paragraph, and R represents a group as hereinbefore defined in respect of R, or R but many in addition represents a group as defined in respect of R9- The reaction conditions for this process may be as described in respect of the reaction of substituted pyridines with ammonia, i.e.1 a temperature in excess of 250C, preferably 350-450C in the presence of a catalyst. The reaction may be carried out batch-wise or as a continuous operation.

The starting materials for use. in the processes of the invention are all substituted pyridine derivatives and the majority of them are novel compounds. Moreover, the subsituted pyridines wherein the substituent has the general formula C( R)(R )(R or -C(R)(R9)(R may be derived from substiuted pyridines wherein the substituent has the formula --CH(R)(R or CH(R)(R,,) respectively and the majority of these substitued pyridines are also novel compounds.

According to a further feature of the present invention, therefore, we provide, as novel compounds, 4-(pyridyl)-tetrahydropyrans or tetrahydrothiopyrans and 2-(pyridyl)-tetrahydropyrans or tetrahydrothiopyrans. The tetrahydropyranyl or tetrahydrothiopyranyl group may be attached to the carbon atom in the 2, 3 or 4 position in the pyridyl nucleus.

According to astill further feature of the present invention we provide, as novel compounds. substituted pyridines wherein the substituent has the structural formula -C(R)(R|)(R )or C(R)(R9l(Rm) wherein the groups R, R,, R R and R are as hereinbefore deand included within the present invention are compounds having this basic formula but containing one or more substituents, for example alkyl or alkoxy groups in either or both of the pyridyl or tetrahydropyranyl nuclei.

Unsubstituted a-(pyridyl)tetrahydropyrans have the structural formula:

and other compounds within the scope of the invention are those wherein either or both of the heterocyclic nuclei are substituted, for example by alkyl or alkoxy groups, especially compounds of formula where R represents an alkyl group, analkoxy group, a heterocyclic group containing a N-heteroatom (which is linked to the carbon atom of the tetrahydropyranyl group) which may also contain one or more other heteroatoms for example a group, or a dialkylamine group for example a -N(CH, group.

The other novel substituted pyridines of the invention have the basic structural formula and included within the scope of the invention are compounds having this basic formula but which contain one or more substituents, for example alkyl groups on one or more of the other carbon atoms of the pyridine nucleus. Also included are compounds of the above basic formula but having a substituent on the nitrogen atom, for example substituted pyridine N-oxides.

4-(pyridyl)-tetrahydropyrans, or -piperidines can be made by reacting a 2-haloethyl-3-(pyridyl)- propylether, thioether or amine respectively with an active alkali metal compound. The reagents are preferably reacted in equimolar proportions and preferably at a temperature in the range lOC to C in solution in a medium containing liquid ammonia. However, the reaction may be carried out in the absence ofa solvent or in solvents other than liquid ammonia, for example hydrocarbons and ethers, in which case higher temperatures, e.g. up to 40C, may be employed. Higher tem peratures can also be achieved by carrying out the reaction under superatmospheric pressure. The preferred active alkali metal compounds are alkali metal amides, especially sodamide.

The 4-(pyridyl)-tetrahydropyran, -tetrahydrothiopyran, or -piperidine may be isolated from the reaction mixture by conventional techniques, for example by decomposing any excess metal amide by additon of an ammonium salt; extract of the resulting product with an organic solvent which is liquid at ordinary temperatures e.g., ether; washing the organic layer with water and separating the organic solvent and the product by distillation.

The 2'-haloethyl 3-(pyridyl)propyl ethers, thioethers I and amaines are novel compounds. In their unsubstituted forms these compounds have the general struc-' tural formula CH CH CH -A-CH CH Hal N metal compound e.g. an alkali metal amide (produced for example by dissolving an alkali metal in liquid ammonia in the presence offerric ions) or an alkyl derivative of an alkali metal e.g. a lithium alkyl. The preferred method of making the alkali metal derivative of the picoline comprises interaction of equimolar proportions of sodamide or potassamide with the picoline which, if the 4-pyridyl derivative is required is a 4-(or gamma)- picoline, at a temperature in the range 40C to 80C in solution in a medium containing liquid ammonia. The reaction may be carried out under pressure to enable temperatures above 30C to be employed.

The alkali metal derivative of the picoline may be reacted with the di-(Z-haloethyhether, thioether or amine by addition of the former to the latter and ensuring a stoichiometric excess of the latter throughout the reaction. The addition may conveniently be carried out at a temperature of from l(JC to 80C preferably using equimolar proportions of the reagents. However. temperatures of up to 40C may be employed. if necessary by carrying out the reaction under increased pressure. The reaction may conveniently be carried out in solution, for example in a solvent comprising or containing liquid ammonia.

The di-( 2-haloethyl)ether, thioether or amine is preferably a di-(2-chloroethyl)ether, thioether or amine.

2-(pyridyl)-tetrahydropyrans or tetrahydrothiopyrans can be prepared by the reaction of the appropriate pyridyl lithium or pyridyl Grignard reagent with a 2-halotetrahydropyran or tetrahydrothiopyran. The pyridyl group becomes attached to the tetrahydropyranyl group by the carbon atom which carried the lithium atom or the Grignard reagent radical. 2-pyridyl lithium can be prepared by reacting 2-chloro-, or preferably 2-bromo-pyridine with n-butyl lithium at low temperatures, for example below 0C and preferably about 40C or lower. 4-pyridyl lithum can similarly be prepared from 4-bromoor 4-chloro-pyridine. 2 pyridyl Grignard reagents are easily prepared by reacting 2bromo-pyridine with e.g. magnesium in the presence of an alkyl halide, eg an alkyl bromide by the entrainment' procedure of Overhoff and Proost (Rec. Trav. Chim. 57, 179, (l938)). 4-pyridyl Grignard reagents can similarly be prepared from 4-bromopyridine. In each case the reagents need simply be mixed but if desired an inert organic solvent may be employed. Any inert solvent may be used, for example aliphatic or aromatic hydrocarbons, ethers and ketones, but in view of the low temperatures employed the solvent preferably has a freezing point of below 50C.

The pyridyl and/or the tetrahydropyranyl or tetrahydrothiopyranyl nuclei may be substituted and examples of substituents which may be present are halogen atoms. alkyl groups and alkoxy groups, and the tetrahydropyran or tetrahydrothiopyran may also carry a heterocyclic substituent. In particular, the tetrahydropyran may have the formula where Y represents a chlorine atom or a bromine atom. Z represents a halogen or a hydrogen atom, and B represents a hydrogen atom, an alkyl or alkoxy group (especially a methoxy group), a heterocyclic group e.g. of formula or an amine grup e.g. N(CH The stereochemistry of the tetrahydropyranyl is not important.

The reaction between the pyridyl lithium or pyridyl Grignard reagent and the 2-halo-tetrahydropyran or tetrahydrothiopyran can be effected simply by mixing the reagents but if desired either or both of the reagents may be employed in the form of a solution. It is an advantage that the reagents do not require to be separated from the reaction mixture in which they have been prepared and thus if they are prepared in solution it is sufficient simply to mix the resulting solutions. The temperature will usually be maintained below 0C and preferably about 40C or below since the reagents tend to be unstable at ordinary temperatures.

The Z-pyridyl tetrahydropyrans or tetrahydrothiopyrans wherein B of the tetrahydrothiopyranyl residue (see above) is a hydrogen atom can be separated from the reaction mixture in which they have been prepared by allowing the mixture to warn to room temperature, acidifying it for example by adding hydrochloric acid, and separating the resulting organic and aqueous pha' ses. The organic phase is then neutralised and extracted with either, and the extract fractionally distilled to re- I cover the fairly pure product which can be purified by further fractional distillation.

The product wherein B of the tetrahydrothiopyranyl residue (see above) is other than a hydrogen atom can be separated by adding an ammonium salt of an acid and then separating the resulting phases, extracting with ether and distilling as above. The ammonium salt, for example ammonium chloride, is preferably used in the form ofa solution which advantageously can be an aqueous solution.

Substituted pyridines wherein the substituent has the structural formula -C(R)(R (R- or C(R)(R )(R can be prepared by reacting the appropriate pyridine derivative with a metal amide or an organo-lithium compound and with an appropriate halogenated organic compound or (if a group CH .C- H20, -CH .CH Sl-l or CH CH NH is to be introduced) with an alkylene-oxide, -sulphide or -imine. Particular combinations of pyridine derivatives and chlorinated organic compounds or alkylene compounds are discussed in more detail hereinafter.

Pyridyl alkane diols, pyridyl alkane dithiols or pyridyl alkane diamines can be prepared by reacting an alkyl pyridine with a metal amide or an organolithiums compound and with an alkylene oxide, alkylene sulphide or alkylene imine respectively. This process is especially suitable for the production of 3-(4'-pyridyl)-pcntanel,5-diol;3-(4'-pyridyl)-pentane-l,S-dithiol or 3-(4 pyridyl)-pentane-l,S-diamine by reacting gammapicoline with a metal amide or an organolithium compound and with ethylene oxide, ethylene sulphide or ethylene imino respectively.

The reaction can if desired be carried out simply by mixing the reagents in appropriate amounts in the absence of a solvent, but usually it is carried out in a solvent for the pyridine derivative. Any solvent may be employed which is inert to the reactants and to the reaction product. Alternatively an excess of the alkyl pyridine or alkanolpyridine or of pyridine itself may be provided to act as a solvent. A particularly suitable solvent for use in reactions involving a metal amide is liquid ammonia although others, for example organic amines such as diethylamine may be used. Examples of solvents which may be used with an organolithium compound is employed are hydrocarbons, especially aliphatic ethers, and particularly diethyl ether, and dimethyl sulphoxide, especially a solution of the sodium salt of dimethyl sulphoxide in excess dimethyl sulphoxide.

The temperature at which the reaction is carried out is to some extent dependent upon the particular solvent employed and the pressure at which the reaction is effected. Thus when liquid ammonia is employed as the solvent at ordinary pressure, the temperature should be -3 3C or below but temperatures above this, for example up to room temperatures may be employed using an amine or an ether as the solvent. Usually, however, the reaction is carried out at a temperature below 40C.

Temperatures higher than those mentioned above may be used, and these can be achieved by carrying out the reaction under superatmospheric pressure, for example in an autoclave.

The metal amide may be in particular an alkali metal amide, particularly sodamide or potassamide. The amide may be added as the pre-formed compound or it may be formed in situ. For example sodamide or potassamide can be formed in situ by adding metallic sodium or potassium to anhydrous liquid ammonia in the presence of a catalyst, for example ferric nitrate (ferric ions). The organolithium compound may be in particular a lithium alkyl, for example lithium ethyl or lithium butyl, or a lithium phenyl or lithium benzyl.

As stated hereinbefore the new compounds of the invention can be prepared from a pyridine derivative and the appropriate halogenated organic compound. Pyridine derivatives which may be used include those of formula R1 (or R9) R (or R) m) 011(3) s Q wherein R, R R R and R are as hereinbefore defined.

The halogenated organic compounds which can be reacted with the pyridine derivative have the formula D Hal wherein D represents R R R or R as hereinbefore defined and Hal is a halogen atom, especially a chlorine atom. The product obtained by reacting pyridine derivative (a) with halogenated organic compound D Hal can have the formula depending upon whether one mole or two moles of D Hal are employed per mole of the pyridine derivative.

The pyridine derivatives (b) and (c) (prepared for example as described in the immediately preceding paragraph) can be reacted with the organic compound D Hal to form the compound (d). Alternatively the compounds (d) can he prepared by reacting pyridine derivatives (b) with a metal amide or an organolithium compound and an alkylene oxide, alkylene sulphide or alkylene imine, particularly an ethylene compound. The use of alkylene compounds having 3 or more carbon atoms has the advantage that the aliphatic group introduced into the pyridine nucleus may have an alkyl group as substituent; bipyridyls wherein the pyridine nuclei carry alkyl substituents can be obtained from these derivatives.

A particular pyridine derivative which can be used is 1-(4-pyridyl)-n-propan 3-0] or -thiol which can be produced by reacting gamma picoline with a metal amide and with ethylene oxide or ethylene sulphide in amounts such that the mole ratio of metal amides gamma picoline is about 1:1 and of ethylene compoundzgamma picoline is also about 1:1.

The products can be separated from the reaction mixture in which they are formed in any convenient manner. For example, especially if the compound has been prepared in liquid ammonia, ammonium chloride can be added and the ammonia (or other solvent) removed by evaporation. The amount of ammonium chloride is usually at least 1 mole per mole of product to be separated. The residue is extracted with a solvent, for example pyridine, methylene chloride or diethyl ether which is then allowed to evaporate. The reaction product is then isolated from the residue by fractional distillation under reduced pressure. In the case where pyridyl alkane diols, dithiols or diamines are prepared from gamma picoline and alkylene oxide, sulphide or imine respectively, the amounts of the metal amide or organolithium compound and of the alkylene derivative used are preferably at least 2 moles of the alkylene derivative and at least 2 moles of the metal amide or organolithium compound per mole of the alkylpyridine. It is especially preferred that the amounts of both the alkylene derivative and the metal amide or organolithium compound are slightly above 2 moles per mole of the alkyl pyridine. The metal amide or the organolithium compound can be added before the alkylene derivative or the three reagents can be mixed together ini tially.

Pyridyl tetrahydropyrans or tetrahydrothiopyrans can also be prepared by heating the appropriate pyridyl alkane diol or dithiol at a temperature of at least 250C, preferably in the presence of a catalyst. Pyridyl piperidines can be prepared by heating the appropriate pyridyl alkane diol, dithiol or hydroxyl thiol in the presence of ammonia; in this case the temperature should be below that at which dehydrogenation of the piperidyl group can occur. Pyridyl tetrahydrothiopyrans can also be prepared by heating the appropriate pyridyl alkane diol in the presence of hydrogen sulphide. or by heating a pyridyl alkane (hydroxy thiol) in the presence or absence of hydrogen sulphide.

The simplest pyridyl alkane diol and dithiol which may be used are 3-(pyridyl)-pentane-l,5-diol or dithiol. The diol or dithiol may be employed without isolation from the mixture in which it has been prepared. The temperature at which the diol or dithiol is heated to convert it to the corresponding pyridyl cyclic. ether, pyridyl cyclic thioether or pyridyl piperidine (if ammonia is present) is at least 250C, and preferably is at least 300C. We especially prefer to employ a temperature ot'the order of 380C. It is sufficient simply to heat the diol or dithiol in the presence of a dehydration catalyst. for example alumina. silica. silica/alumina or mixtures thereof. A particularly convcnientn technique is to pass the diol or dithiol in vapour phase through a bed of the catalyst contained in a tube, for example a glass tube. If desired the heating may be carried our under super-atmospheric pressure, in which case lower temperatures may be needed to effect the conversion. Am-

monia or hydrogen sulphide may be added to or dis solved in the diol or dithiol so that the product of heating the diol or dithiol is the corresponding pyridyl piperidine or pyridyl alkane dithiol respectively.

The invention is illustrated but in no way limited by the following Examples:

EXAMPLE 1 To stirred liquid ammonia (3litres) was added ferric nitrate (0.1 gm) followed by sodium metal (24 gms in 1 gm pieces over a period of 40 minutes). To the resulting solution gamma-picoline (46.6 gms) was added over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Liquid ethylene oxide (44.0 gms) was added and the mixture was stirred for a further 8 hours. Solid ammonium chloride (55 gms) was added in small quantities and the sol vent was allowed to evaporate overnight. The tacky residue was extracted into pyridine and the pyridine was then evaporated. The residual oil was dissolved in an equal quantity of hot water and dropped onto a bed of alumina (Actal A) heated at 380C at the rate of l ml/minute using a 300 ml/minute flow of nitrogen "as carrier gas. The effluent was condensed and the condensate extracted into carbon tetrachloride. Evaporation of the solvent followed by distillation yielded 4(4 -pyridyl)-tetrahydropyran (19 gms 42 percent con version based on gamma-nicoline fed).

EXAMPLE'2 To stirred liquid ammonia (300 mls) was added ferric nitrate (50 mgms) and sodium metal (1.2 gms). The mixture was allowed to stand for 30 minutes and then gamma-picoline (4.7 gms) was added. A deep yellow colour was allowed to develop over a period of 2 hours. Cooled ethtylene oxide (2.2 gms) was then added and the mixture was stirred for a further 4 hours, yielding a solution designated Solution A.

To stirred liquid ammonia (200 mls) was added ferric nitrate (50 mgms) and sodium metal (1.2 gms). The mixture was allowed to stand for 30 minutes and was then added over a period of 2 minutes to Solution A. The mixture was stirred for a further 4 hours after which time solid ammonium chloride (6 gms) was added slowly. The solvent was allowed to evaporate overnight and the residue was extracted into methanol 100 mls) and filtered.

The filtrate was vaporised at mls/hr and fed in a stream of nitrogen carrier gas 100 mls/minute) over a 4 inch bed of 13 percent silica-alumina in a 1 inch glass tube at a temperature of 340C. The liquid effluent was analysed by gas/liquid chromatography and was found to contain 4-(4-pyridyl)-tetrahydropyran (62 percent conversion).

EXAMPLE 3 To stirred liquid ammonia (300 mls) was added ferric nitrate (50 mgms) and potassium metal (2.0 gms). The mixture was allowed to stand for minutes after which time gamma-picoline (4.7 gms) was added. A deep yellow colour was allowed to develop over a period of 2 hours. Cooled ethylene oxide (2.2 gms) was then added and the mixture was stirred for a further 4 hours. yielding a solution designated Solution B."

To stirred liquid ammonia (200 mls) was added ferric nitrate (50 mgms) and potassium metal (2.0 gms). The mixture was allowed to stand for 30 minutes and added over a period of 2 minutes to Solution B. The mixture was stirred for a further 4 hours after which time solid ammonium chloride (6 gms) was slowly added. The solvent was allowed to evaporate overnight and the residue was extracted into methanol mls) and filtered.

The filtrate was vaporised at 25 mls/hour and fed in a stream of nitrogen carrier gas (100 mls/minute) over a 4 inch bed of 13 percent silica-alumina in a 1 inch bore glass reactor tube at a temperature of 340C. The liquid reactor effluent was analysed by gas/liquid chromatography and was found to contain 4-(4-pyridyl)-tetrahydropyran (58 percent conversion based on gamma-picoline fed).

EXAMPLE 4 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (18.5 gms) in 1 gram pieces over a period of 30 minutes. The mixture was allowed to stand for 30 minutes and then gamma-picoline (37.3 gms) was added to it. A deep yellow colour was allowed to develop over 2 hours, after which time ethylene sulphide (48.0 gms) was added as quickly as possible. The resulting solution was stirred for a further 4 hours after which ammonium chloride (50 gms) was slowly added, followed by diethyl ether (1 litre). The ammonia was allowed to evaporate and the residual solution was filtered. The solvent was evaporated from the filtrate and the residue was distilled to yield 3-(4-pyridyl)-pentane l,S-dithiol (18 gms) as a yellow oil ofb.p. 163165C. The product had the following spectra:

[.R. 1 max (CCl 3100, 3050, 2950, 2850, 2500, 1600, 1440, 1430, 1410, 1270 and 1075 cm NMR T (CCl 1.45, 2.8, 78.5 (Relative Intensities 212:] 1).

MS. Me 213.0646), 179.

A low-boiling by-product of the reaction was identified as 3-(4-pyridyl)-propane-l-thiol (b.p. 8486C/l mm. Hg) identified by the following spectra:

[.R. v max (liquid film) 3100, 3050, 2950, 2850, 2550, 1600 1430, 995 and 810 cm MS. M/e 153.0613 (C H NS has 153.0612).

213.0658 c H,,Ns has M/e EXAMPLE 5 Ferric nitrate (0.1 gm) was added to stirred liquid ammonia (3litres) at 30C. Sodium metal (24 gms) was added to the stirred mixture over a period of 45 minutes and then gamma-picoline (46.6 gms) was added to the resulting solution over a period of 3 minutes. The solution was stirred for 2 hours during which time it developed a yellow colouration.

After this time liquid ethylene oxide (44.0 gms) was added and the mixture was then stirred for 8 hours. Solid ammonia chloride (55 gms) was then added in small quantities after which the mixture was allowed to stand overnight to allow the ammonia to evaporate. The resulting tacky residue was extracted into pyridine which was then removed by evaporation, leaving a liquid which on distillation yielded 3-(4-pyridyl l-pentane- 1,5-diol (66 gms), representing a conversion of 73 percent based on the gamma-picoline fed. The product at this stage had a boiling range of 182 to C at 0.5 mm Hg pressure, and a melting range of 66 to 68C.

After recrystallisation from water the product had a melting point of 72 to 73C.

The 3-(4-pyridyl)-pentane-l,5-diol was identified by the following infra-red (lR), nuclear magnetic resonance (NMR) and mass (MS) spectra:

1R (melt) 3500, 2950, 2850, 1600, 1420, 1050, 1005 cm".

NMR 'r(CD OD) 1.52, 2.65, 5.05, 6.6, 6.95, 8.1 (Relative Intensities 2:2:2:4:1:4).

MS M/e 181.1103 (C H N has M/e 181.1102).

EXAMPLE 6 To stirred liquid ammonia (3 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (24 gms) in 1 gram pieces over a period of 30 minutes. The resulting solution was stirred for 30 minutes after the final addition of sodium metal and then a solution of gamma-picoline (46.6 gms) and ethylene oxide (48 gms) in ice-cold diethyl ether (100 mls) was added over a period of 2 hours. The mixture was stirred for a further 2 hours and then solid ammonium chloride (55 gms) was added. The solvent was allowed to evaporate overnight and the residual tacky solid was extracted into pyridine. Evaporation of the pyridine followed by frac tional distillation yielded 3-(4-pyridyl)-pentane-1,5- diol of boiling range 200 to 202C at 1 mm Hg pressure and melting range 66 to 68C (56 grns, 62 percent conversion of gamma-picoline fed).

EXAMPLE 7 Sodamide (25 gms), gamma-picoline (24 gms) and ethylene oxide (24 gms) were introduced into a pressure vessel cooled to 0C. The vessel was sealed and heated to +C and was then maintained at +20C with vigorous stirring for 6 hours. After this time the pressure was then released and methanol (50 mls) was introduced slowly, followed by dilute hydrochloric acid (200 mls). The solution was evaporated to dryness, neutralised with aqueous potassium carbonate solution and again evaporated to dryness. The residual tacky solid was extracted into pyridine, the solvent was evaporated and the residual oil was distilled to yield 3-(4- pyridyl)-pentane-l,5-diol (8 grns, 18 percent).

EXAMPLE 8 Sodamide gms), gamma-picoline (24 gms) and ethylene oxide (24 gms) were introduced into a pressure vessel cooled to 40C. Liquid ammonia (70 mls) was introduced and the vessel was then sealed. The mixture was heated to +20C and maintained at that temperature, with vigorous stirring, for 2 hours. The ammonia was then vented off. Methanol (50 mls) was introduced slowly, followed by dilute hydrochloric acid (200 mls). The solution was evaporated to dryness, neutralised with aqueous potassium carbonate solution and again evaporated to dryness. The residual tacky solid was extracted into pyridine, the solvent was evaporated and the residual oil was distilled to yield 3-(4- pyridyl)-pentane-1,5-diol (28 gms, 62 percent).

EXAMPLE 9 To stirred liquid ammonia (3 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (24 gms) in 1 gram pieces over a period of minutes. The mixture was allowed to stand for 30 minutes and ethylene oxide (45 gms) was added, followed by alpha-picolinc (45.6

gms). The resulting blood-red solution was stirred for 4 hours and then ammonium chloride (60 gms) was added in small portions. The solvent was allowed to evaporate overnight and the residual oily residue was extracted into pyridine. Evaporation of the solvent and distillation of the residual oil yielded 3-(2-pyridyl)- pentane-1,5-diol (42 grns, 46 percent conversion), M.P. 44C b.p. 176 to 180C at 1 mm Hg.

The product had the following spectra:

1R (liquid film) 3400, 2950, 1595, 1470,1430,1050, 1000 and 755 cm.

NMR 1-[(CD3)2CO] 1.52, 2.38, 282, 5.7, 6.6, 6.85 and 8.1 (Relative Intensities 1:1:2:2:4:1:4).

MS M/e 182, 181.1089 (C H, NO has M/e 181.1102) 180,137,120,118,117,106.

EXAMPLE 10 To stirred liquid ammonia (3 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (40 gms) in 1 gram pieces over a period of 30 minutes. The mixture was allowed to stand for 30 minutes and ethylene oxide (45 gms) was added followed by beta-picoline (456 gms). The resulting dark-red solution was stirred for 24 hours and ammonium chloride (60 gms) was added in small portions. The solvent was allowed to evaporate overnight and the residual oily residue was extracted into pyridine. Evaporation of the pyridine and distillation of the residual oil yielded 3-( 3-pyridyl)- pentane-l ,5-diol (18 gms, 20 percent conversion), b.p. 200 to 210C at 1 mm Hg.

The product had the following spectra:

1.R. (liquid film) 3400, 2950, 2900, 1600, 1460, 1430, 1050, 880, 820 and 720 cm.

M.S. M/e 181.1088 (C H NO 181.1102).

has M/e EXAMPLE 1 1 3-(4-pyridyl)-pentane-l,5-diol (5 gms) was distilled at atmospheric pressure. The distillate was extracted into ether and the solution was washed with water and dried over magnesium sulphate. Evaporation of the solvent and distillation of the residual oil yielded 4-(4-pyridyl)-tetrahydropyran (2.2 grns 58 percent conversion of diol fed).

EXAMPLE 12 A solution of n-butyl bromide (46 g) in dry ether mls) was added slowly to a suspension of lithium wire (2.3 g) in dry ether (200 mls), at a temperature of 20C with vigorous stirring under an atmosphere of nitrogen. Stirring was continued after the addition was completed for 2 /2 hours at 20C. The reaction mixture was then filtered under nitrogen and cooled to be tween 45C and -40C, and 2-bromopyridine (52.7 g) in dry ether (10 mls) was added slowly to the filtrate, the temperature being maintained at 40C. A dry nitrogen atmosphere was maintained, and after the addition was completed, stirring was continued at 40C for 2 hours (Solution A).

A -dihydropyran (28 g) in dry ether (100 mls) was cooled to 10C and dry hydrogen chloride gas 12.2 g) was passed into it at such a rate that the temperature did not rise above -l0C. The solution was cooled to -40C and added slowly, with stirring, under nitrogen to Solution A also cooled to 40C. Stirring was continued for 1 hour at 40C, and the reaction product was then allowed to warm to room temperature. Hydrochloric acid (200 mls of 2N HCl) was added and the mixture was separated. The acidic fraction was neutralised with sodium carbonate solution and extracted with ether. The extracts were washed, dried and fractionally distilled to yield:

a. 2-bromo pyridine b.p. 66 to 80C/3.5-5mm Hg (25 g, 48 percent).

b. Product (14 g, 26 percent conversion, 52 percent yield).

The product had a boiling range of 70 to 73C/1 mm Hg.

The product was identified as 2-(2'-pyridyl)- tetrahydro pyran by the following infra-red, mass (MS) and nuclear magnetic resonance (NMR) spectra:

Infra-red: max (liquid film) 2940,2840, 1600, 1460, 1430, 1200, 1070, 1040, 1110, 910 and 765 cm.

N.M.R. 'r(CCl,) 1.55, 2.5, 2.95, 5.65, 5.9, 6.45, 8.5 (Relative intensities l:2:l:l:l:l:6).

M.S. M/s 163.0997 (C H NO has M/e 163.0997), 106,93, 85,79.

Using alpha-picoline instead of gamma-picoline in the preparation of Solution A, and continuing the reaction under the conditions outlined above yielded l-(2- chloroethoxy)-3-(2-pyridyl)-propane (25 gms) b.p. 105 to 1 C/15 mm Hg, characterised by the following spectral data:

l.R. (liqudi film) 2950, 2850, 1580, 1470, 1430, 1120, 770 and 750 cm".

N.M.R. 1' (CCl,) 1.5, 2.5, 2.95, 6.43, 6.54, 7.15, 8.0 (Relative intensities 1:1:2:4:2:2:2).

M.S. M/e 199, 198.0680 (C H NOCl has M/e 198.0685, loss of H), 164.

Using beta-picoline instead of gamma-picoline in the preparation of Solution A, and continuing the reaction under the conditions outlined above yielded 1-(2- chloroethoxy)-3(3-pyridyl)-propane (8 gms as an unstable straw-coloured liquid).

M.S. M/e =199.

EXAMPLE 13 To stirred-liquid ammonia (1 litre) was added ferric nitrate (0.1 gram) followed by potassium metal (200 grams) in 1 gram pieces over a period of 30 minutes. To the resulting solution gamma-picoline (46.6 grams) was added over a period of 3 minutes and a deep yellow colour was allowed to develop.

The solution was added to a stirred solution of 2.2'-di(chloroethyl)-ether (72.0 grams) in liquid ammonia (1 litre) at such a rate (total addition taking 20 minutes) that no yellow colour persisted, yielding a solution designated Solution A.

To stirred liquid ammonia (1 litre) was added ferric nitrate (0.1 gram) followed by potassium metal (20.0 grams) in 1 gram pieces over a period of 30 minutes. The resulting solution was stirred for 20 minutes and added to Solution A at such a rate that only a pale yellow colour developed. The mixture was stirred for 1 hour and ammonium chloride (20 grams) was added slowly followed by ether 1 litre). The mixture was allowed to warm to room temperature, was filtered, and washed with water. The solvent was removed and the residue was distilled to give 4-(4-pyridyl) tetrahydro pyran (30 grams) having the following properties:

Boiling point 115118C/1 mm Hg.

Melting point 6062C.

Infra-red 11 max (liquid film) 3070, 3025,2940, 2845, 1600, 1410, 1130, 1085, 990 and 900 cm.

NMR 1' (CDCl 1.5, 2.85, 5.9, 6.5, 7.25, 8.25 (Relative intensities 2:2:2:2:1 :4).

Mass spectra: M/e=163.0998 (C H NO has M/e 163.0997) 132, 130, 119, 105, 92 and 78.

A higher boiling fraction (5 gms) was also collected and identified as di-3-(4-pyridyl)-prop-l-yl ether b.p. 215C/1 mm Hg.

Infra red v max (CCl 3070, 3025, 2940, 2845, 1600, 1410, 1120, 990 and 900 cm.

NMR 1-[(CD CO]: 1.35, 2.7, 6.5, 7.2, 8.1 (Relative intensities 4:4:4:4:4).

M.S. M/e 256.1578 (CwHguNgO has M/e Similarly from alpha-picoline was obtained 4(2- pyridyl) tetrahydropyran identified by the following spectral data:

M.S. M/e 163 (C H NO has M/e 163).

Also obtained from this reaction was vinyl 3-(2- pyridyl)-prop-l-yl ether b.p. 85C/0.5 mm Hg identified by the following spectral data:

l.R. (liquid fi1m)'3050, 2950, 2850, 1640, 1620, 1580, 1560, 1460, 1430,1300, 1195, 990, 820, 770 and 750 cm.

N.M.R. r (CCl,) 1.55, 2.5, 3.0, 3.6, 5.95, 6.15, 6.4, 7.2 and 7.95 (Relative intensities 1:l:2:1:1:1:2:2:2).

MS. M/e 163.0985 (C H NO has M/e Similarly from beta-picoline was obtained 4-( 3-pyridyl) tetrahydropyran, m.p. 340C identified by the following spectral data:

[.R. 11 max (CC1,) 2950, 2850, 1460, 1440, 1430, 1375, 1120, 1090, 1020 and 900 cm".

N.M.R.r(CCl,)1.5,2.5, 2.8, 5.95, 6.5, 7.2 and 8.25 (Relative intensities 2:1:1:2:2:1:4).

M.S. M/e 163.1004 (C H NO has M/e 163.0997).

EXAMPLE 14 Solution A prepared as in Example 13 was stirred for 1 hour and ammonium chloride (20 gms) was added slowly followed by ether (1 litre). The mixture was allowed to warm to room temperature, was filtered and washed with water. The solvent was removed by distillation under vacuo and the residue was heated at C/1 mm Hg to remove starting materials. The resi due was purified by column chromatography to give 1- (2-chloroethoxy)-3-(4-pyridyl) propane (60 grams) an amber-coloured liquid, which could not be distilled without decomposition and which had the following properties:

Infra-red 11 max (liquid film) 3075, 3020,2950, 2860, 1600, 1415, 1300, 1120, 990, 800 and 660 cm.

NMR'r(CC1,) 1.5, 2.85, 6.3, 6.55, 7.3, 8.15 (Relative intensities 2:2:4:2:2:2).

MS. M/e 199.0751 199.0763

(C H NClO has M/e EXAMPLE 15 To stirred liquid ammonia 1 litre) was added ferric nitrate (0.1 gm) followed by potassium metal (4.5 gms) in 1 gram pieces over a period of5 minutes. The result ing solution was allowed to stand for 30 minutes and was then added with stirring to a solution of 2-chloroethyldimethylamine hydrochloride (14.4 gms) in liquid ammonia (1 litre). The resulting solution was designated Solution A.

To stirred liquid ammonia (1 litre) was added ferric nitrate (0.1 gm) followed by potassium metal (4.5 gms) in 1 gram pieces over a period of 5 minutes. The mixture was allowed to stand for minutes and 3-(4- pyridyl)-propionaldehyde diethyl acetal (21 gms) was then added over a period of 2 minutes. A yellow colour was allowed to develop over a period of 2 hours, and after this time the solution was added to Solution A.

The resulting mixture was stirred for 3 hours after which time solid ammonium chloride (8 gms) was added followed by diethyl ether (500 mls). The ammonia was allowed to evaporate overnight and the residual mixture was then filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield 3-(4-pyridyl)-1,1-diethoxy-S-dimethylamino pentane (18 gms, 72 percent conversion of starting material fed); b.p. 140C/1 mm Hg pressure.

The product was identified by the following infra red (1R), nuclear magnetic resonance (NMR) and mass (MS) spectra:

l.R. (liquid film) 2950, 2850, 2780, 1600, 1120, 1069, 1000 and 820 cm".

N.M.R. 'r(CCl 1.5, 2.9, 5.8, 6.55, 7.15, 7.9, 8.05, 8.85 (Relative intensities 2:2:1:4:l:8:4:6).

M.S. M/e 280, 251.1759 (C H N O has M/e 251.1752, loss of C H EXAMPLE 16 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (12 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution was added 3-(4-pyridyl)-1- dimethylamino pentane (49 gms) over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Liquid ethylene oxide (22 gms) was added and the mixture was stirred for a further 3 hours. Solid ammonium chloride (20 gms) was then added in small portions followed by diethyl ether 1 litre). The ammonia was allowed to evaporate overnight and the residual mixture was then filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield 6-(4-pyridyl)-8- dimethylamino-3-oxaoctan-l-ol gms, percent cconversion ofstarting material fed) b.p. l40148C/l mm Hg.

1R. (liquid film) 3400, 2950, 2850, 2800, 2780, 1600, 1450, 1400, 1120, 1050, 1000 and 825 cm.

N.M.R. 1-(CCl 1.6, 2.9, 5.5, 6.45, 6.65, 7.2, 7.95, 8.25 (Relative intensities 2:2:1:2:4:l:8:4).

M.S. M/e 252.1835 (C ,H ,N- O has M/e 252.1837).

EXAMPLE 17 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (8.0 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution was added 3-(4-pyridyl)-1- dimcthylaminopentane (49 gms) over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Liquid ethylene oxide (14.6 gms) was then added and the mixture was stirred for a further 3 hours. Solid ammonium chloride (20 gms) was then added in small portions, followed by diethyl ether 1 litre). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield 3-(4-pyridyl)-5- dimethylamino pentan-l-ol (32 gms, 46 percent conversion) b.p. l40l46C/0.5 mm Hg (m.p. 26C),

l.R. (liquid film) 3400, 2950, 2850, 2800, 2780, 1600, 1450, 1400, 1050, 1000 and 825 cm.

N.M.R.r(CCl,)1.6, 2.9, 5.0, 6.7, 7.2, 7.95, 8.1 (Relative intensities 2:2:1:2:l:8:4).

M.S. M/e 208.1585 (C H- N has M/e 208.1575).

EXAMPLE 18 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (20 gms) in 1 gram pieces over a period of 20 minutes.The resulting solution was added with stirring to a solution of (2-chloroethyl)-dimethylamine hydrochloride (72 gms) in liquid ammonia (1 litre). This solution was designated Solution A.

To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (20 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution was added gamma-picoline (23 gms) over a period of 3 hours. The resulting solution was then added to Solution A and the resulting mixture was stirred for 3 hours. Solid ammonium chloride (60 gms) was then added, followed by ether 1 litre). Theammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield 3- (4-pyridyl)-1,S-bisdimethylaminopentane (23 gms, 40 percent conversion); b.p. l11l20C/1 mm Hg. l.R. (liquid film) 2950, 2850, 2780, 1600. 1460. 1410, 1040 and 830 cm.

N.M.R. 1' (CCL) 1.55, 2.9, 7.2, 7.9, 8.2 (Relative intensities 2:2:1zl6z4).

M.S. M./ 235.2044 (C H N has M/e 235.2048).

EXAMPLE 19 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by sodium meta] (4.6 gms) in 1 gram pieces over a period of 5 minutes. The resulting solution was allowed to stand for 20 minutes and. 3-(4 pyridyl)-1-diethylaminopentane (38.4 gms) was added. A deep yellow colour was allowed to develop over a period of 3 hours. Solid ammonium chloride (20 gms) was added in small portions and the ammonia was allowed to evaporate overnight. The residual tacky oil was extracted into methylene chloride, filtered and the solvent was evaporated from the filtrate. Distillation of the residual oil gave 3-(4-pyridyl)-5-diethylaminopentan-l-ol (39 gms, 83 percent conversion) b.p. -177C/2.0 mm Hg.

l.R. (liquid film) 3400, 2950, 2850, 2800, 2780, 1600, 1400, 1360, 1050 and 820 cm.

N.M.R. 'r(CDCl 1.55, 2.83, 4.75, 6.52, 7-8.5, 9.05 (Relative intensities 2:2:l:2:1 1:6).

M.S. M/e 236.1885 (C ,,H N O has M/e 236.1888).

EXAMPLE 20 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (20 gms) in 1 gram pieces over a period of 20 minutes. The resulting solution was added with stirring to a solution of 2-chlor0triethylamine hydrochloride (86 gms) in liquid ammonia 1 litre). This solution was designated Solution A."

To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (20 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution was added gamma-picoline (23 gms) over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. The resulting solution was added to Solution A and the resulting mixture was stirred for 3 hours. Solid ammonium chloride (60 gms) was then added followed by diethyl ether 1 litre). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield 3-(4-pyridyl)-l ,5-bisdiethylaminopentane (32 gms, 44 percent conversion) b.p. 153-154C/1.5 mm Hg.

l.R. (liquid film) 2950, 2850, 2800, 2780, 1600, 1450, 1400, 1360, 1190, 1075, 1060 and 820 cm.

N.M.R. r (CCL) 1.65, 3.02, 7.30, 7.65, 7.85, 8.3, 9.1 (Relative intensities 2:2:l:8:4:3:2:12).

M.S. M/e 291.2690 (C ,,H N has M/e 291.2674).

EXAMPLE 21 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal (20 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution, gamma-picoline (23 gms) was added over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Vinyl chloroethyl ether (53 gms) was then added over a period of 30 minutes and the mixture was stirred for a further 5 hours. Solid ammonium chloride (25 gms) was then added in small portions followed by diethyl ether (1 litre). The ammonia was allowed to evaporate overnight and the residual mixture was filtered.

The solvent was evaporated from the filtrate and the residual oil was distilled to yield 6-(4-pyridyl)-3,9-dioxa-undeca-l,10-diene (59 gms, 50 percent conversion) b.p. 141143C/l.5 mm Hg.

1.R. (liquid film) 3050, 2950, 2850, 1640, 1620,

- 1600, 1400, 1310, 1190, 990, 960 and 820 cm.

N.M.R. r(CC1,) 1.45, 2.85, 8.60, 6.0, 6.15, 6.5, 7.05, 8.05 (Relative intensities 2:2:2:2:2:4:1:4).

M.S. M/e 233.1421 (C H NO has M/e 233.1416).

EXAMPLE 22 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution gamma-picoline (46.6 gms) was added over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Vinyl chloroethyl ether (53 gms) was added as quickly as the exothermic reaction allowed and the mixture was stirred for a further 2 hours. Solid ammonium chloride gms) was then added in small portions, followed by 1 diethyl ether (1 litre). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to yield vinyl 3-(4-pyridyl)- prop-l-yl ether (61 gms, 75 percent conversion); b.p. 90-96C/1 mm Hg.

1.R. (liquid film) 3050, 2950, 2850, 1640, 1620. 1600 1400, 1310. 1195.990 and 820 cm.

N.M.R. r( CC1 1.55, 2.95, 3.53, 5.9, 6.06, 6.4, 7.35. 8.1 (Relative intensities 2:2:1:l:1:2:2:2).

M.S. M/e 163.0991 (C H NO has M/e 163.0997).

The distillation residue was shown to contain 6-(4- pyridyl)'3,9-dioxa-undeca-1,IO-diene.

EXAMPLE 23 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by potassium metal 14 gms) 5 in 1 gram pieces over a period of 20 minutes. To the resulting solution 3-(4-pyridyl)-propionaldehyde diethyl acetal (21 gms) was added over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Liquid ethylene oxide (25 mls) was then added and the mixture was stirred for a further 3 hours. Solid ammonium chloride (20 gms) was added in small portions followed by diethyl ether (1 litre). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to give 1,1-diethoxy-3-(4-pyridyl)-pentan-5-ol 18 gms, 70 percent conversion) b.p. 170175C/1 mm Hg, as a thick colourless oil.

LR. (liquid film) 3400, 2950, 2850, 1600, 1400, 1130, 1055 and 1000cm.

N.M.R. -r(CCl,,) 1.55, 2.85, 5.55, 5.85, 6.6, 7.05, 8.2. 8.85 (Relative intensities 2:2:1:1:6:1:4:6).

M.S. M/e 253.1671 (C H NO has M/e 263.1677) 7 EXAMPLE 24 To a stirred suspension of sodamide (3.9 gms) in 3-(4-pyridyl)-propionaldehyde diethyl acetal (200 gms) was added dropwise, under nitrogen, chloroacetal (15.2 gms) at such a rate that the temperature did not exceed C. The mixture was allowed to stand for 20 hours after which time saturated aqueous ammonium chloride was added dropwise until no further reaction occurred. The organic layer was separated and the aqueous phase was extracted several times into diethyl ether. The organic extracts were combined and dried and the solvent was evaporated. Distillation of the residual oil yielded starting pyridylpropionaldehyde acetal (13 gms, 65 percent recovery) and a fraction (6 gms, 12 percent conversion) identified from its spectra as 3-(4-pyridyl)-glutaraldehyde tetraethyl acetal; b.p. 149-154C/1 mm Hg.

l.R. (liquid film) 3020. 2950, 2850, 1600, 1420,- 1370, 1150, 1130, 1065 and 1000 cm.

N.M.R. r(CCL 1.55, 2.9, 5.7, 6.6, 7.2, 8.15, 8.9 (Relative intensities 2:2:2:8:l:4:12).

M.S. M/e 325.2240 (C ,,H NO has M/e.325.2252).

EXAMPLE 25 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (2.3 gms) in small pieces. The mixture was allowed to stand for 30 minutes and 3-(4-pyridyl)-propionaldehyde diethyl acetal (20.0 gms) was then added. A deep yellow colour was allowed to develop over a period of 2 hours, after which time ethylene sulphide (6.0 gms) was added quickly. A vigorous reaction occurred and the mixture was stirred for a further 5 hours. Ammonium chloride (7 gms) was added and the solvent was allowed to evaporate overnight. The residual tacky solid was extracted into pyridine and filtered and the solvent was evaporated from the filtrate. Distillation of the residual oil yielded 3-(4-pyridyl)-5,5-diethoxy-pentane-1-thiol (17 gms, 63 percent conversion) b.p. 167l72C/1 mm Hg, characterised by the following spectra:

1.R. vmax (liquid film) 2950, 2850, 2550, 1600. 1400, 1120, 1050, 990 and 820 cm.

19 M.S. M/e 269.1469 weak (C I-1 N has M/e 269.1449), 223.1033 (C H NOS has M/e 223.1031) and 103.0760 C H O has M/e 103.0758).

N.M.R. r(CCL 1.55, 2.9, 5.9, 6.6, 7.15, 7.8, 8.15 (Relative intensities 2:2:l:4:1:2:4:1:6).

EXAMPLE 26 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (6.3 gms) in small pieces. The mixture was allowed to stand for 30 minutes and 3-(4-pyridyl)-propan-l-ol (19 gms) was then added. A deep yellow colour was allowed to develop over a period of 2 hours after which time ethylene sulphide (8.3 gms) was added quickly. A vigorous reaction occurred and the mixture was stirred for a further 4 hours. Ammonium chloride gms) was added and the solvent was allowed to evaporate overnight. The residual tacky solid was extracted into pyridine and the mixture was filtered and the solvent evaporated. Distillation of the residual oil yielded 3-(4- pyridyl)-5-hydroxy-pentane-1-thio1 (12.7 gms, 60 percent conversion); b.p. 177185C/1 mm Hg, m.p. 5052C, characterised by the following spectra:

l.R. vmax (melt) 3350, 2950, 2850, 2550, 1600, 1400, 1950, 1000 and 820 cm.

M.S. M/e 197.0974 (CIUH NOS has M/e 197.0873).

N.M.R. r((CD CO) 1.4, 2.65, 7-8.5 (Relative intensities 2:211 1) EXAMPLE 27 To stirred liquid ammonia (2 litres) was added ferric nitrate (0.1 gm) followed by sodium metal (2.3 gms) in small pieces. The mixture was allowed to stand for 30 minutes and 3-(4-pyridyl)-l-diethylamino propane (19.2 gms) was then added. A deep yellow colour was allowed to develop over a period of 2 hours, after which time ethylene sulphide (6.0 gms) was added quickly. A vigorous reaction occurred and the mixture was stirred for a further 5 hours. Ammonium chloride (7 gms) was added, and the solvent was allowed to evaporate overnight. The residual tacky solid was extracted into pyridine and the extract was filtered and the solvent evaporated. Distillation of the residual oil yielded 3-(4-pyridyl)-5-diethy1amino-pentane-l-thiol, (18 gms, 72 percent conversion) b.p. 140-143C/0.2 mm Hg, characterised by the following spectra:

1.R. vmax (liquid film) 2950, 2850, 2760, 2500, 1600, 1400, 1060, 990 and 820 cm.

M.S. M/e 252.1652 (C H N S has M/e 252.1652).

N.M.R. r(CCl -l CDCL 1.45, 2.9, 7.2, 7.6, 7.7, 8.1, 9.1 (Relative intensities 2:2:1:4:4:5:6).

EXAMPLE 28 To stirred liquid ammonia (300 mls) was added ferric nitrate (50 mgs) followed by sodium metal (4.5 gms). The mixture was allowed to stand for 30 minutes and then' 3-(4-pyridyl)-l-amino propane (13.5 gms) was added. A deep yellow colour was allowed to develop over 1 hour and ethylene oxide (5.0 gms) was then added. The mixture was stirred for a further 2 hours after which time solid ammonium chloride (12 gms) was added. The solvent was allowed to evaporate overnight and the residual solid was extracted into pyridine. Evaporation of the pyridine and crystallisation of the residue from benzene yielded 3-(4-pyridyl)-l-amino-5- hydroxy pentane (3.4 gms; 17 percent). Characterised by the following spectral data:

LR. vmax (nujol mull) 3300. 2950, 2850, 1600,

1400, 1050, 990, 820 and 710 cm.

M.S. M/e 180.1259 (C H N O has M/e 180.1262).

EXAMPLE 29 To stirred liquid ammonia (300 mls) was added ferric nitrate (50 mgs) followed by sodium metal gms). The mixture was allowed to stand for 30 minutes and then 3-(4-pyridyl)-propan-1o1 (13.7 gms) in diethyl ether (25 mls) was added. A deep yellow colour was EXAMPLE 30 To stirred liquid ammonia (1 litre) was added ferric nitrate (0.1 gm) followed by sodium metal (12.0 gms) in 1 gram pieces over a period of 30 minutes. To the resulting solution alpha-picoline (23.3 gms) was added followed by 4-chloro butyl acetate (37.5 gms). The mixture was stirred for 4 hours after which time ammonium chloride (30 gms) was added in small pieces.

The solventwas allowed to evaporate and the residue was extracted into diethyl ether, washed with dilute hydrochloric acid, and the extracts were made alkaline. These were then extracted into diethyl ether and dried, and the solvent was evaporated. The residual oil was allowed to stand for 4 days with acetic anhydride (40 ml) and pyridine (40 ml), the solvents were then evaporated. The residue was poured into water, neutralised with potassium carbonate and extracted into diethyl ether. The extracts were dried, the solvent was evaporated, and the residual oil was distilled to yield 5-(2- pyridy1)-pentan-1-y1 acetate b.p. 120-123."C/1 mm Hg (15 gms; 34 percent), identified by the following spectral data: 1.R. (liquid film) 2950, 1740, 1580, 1470, 1440, 1240, 1050, and 760 cm.

N.M.R. -r(CC1,,) 1.7, 1.6, 3.1, 6.1, 7.4, 8.15 and 8.5 (Relative intensities 1:1 :2:2:2:3:6).

M.S. M/= 207.1251 (C I-1 190 207.1259).

has M/e EXAMPLE 31 Aqueous hydrogen peroxide (13 mls of 30 percent solution) was added over 2 hours to a solution of 5-(2- pyridyl)-pentan-1-yl acetate (13.0 gms) in acetic acid (50 mls) at C. After 16 hours the mixture was heated to C and paraformaldehyde (1.8 gms) was added. After a further 2 hours the solvent was evaporated in vacuo and the residual oil was added to acetic anhydride (5O mls) and heated at 95C for 6 hours. The solvent was evaporated and the product was poured onto ice, neutralised with potassium carbonate and extracted into diethyl ether. Evaporation of the ether and distillation of the residual oil yielded I-(Z-pyridyH-l .5- diacetoxy pentane, b.p. l40-l4IC/l mm (8 gms; 40 percent). Characterised by the following spectral data:

LR. (liquid film) 2950, 1750, 1580, 1470, 1430, 1370, 1240, 1200 and 1050 cm.

N.M.R. r(CDCl 1.35, 2.3, 2.75, 4.1, 5.9, 7.85, 8.0 and 8.4 (Relative Intensities 1:l:2:1:2:3:3:6).

M.S. M/e 265.1310 (C H NO, has M/e 265.1314).

EXAMPLE 32 1,S-diacetoxy-1-(2-pyridyl)-pentane (3.0 gms) was suspended in percent sodium hydroxide solution and the mixture was stirred at room temperature for 3 days. The residue was washed with methylene chloride and extracted into butanol. The butanol extracts were evaporated to dryness to leave a waxy solid (1.2 grns; 56 percent) identified as l-(2-pyridyl)-pentane-l ,5- diol by the following spectral data:

1.R. (liquid film) 3300, 2950, 2850, 1580, 1560, 1470, 1430, 1280, 1070 and 1020 cm".

M.S. M/e 181.1108 (C H NO has M/e 181.1 102 EXAMPLE 33 A solution of benzoyl peroxide (50 mgs) and redistilled 4-(4-pyridyl)-tetrahydropyran (5.0 gms) in dry carbon tetrachloride (50 mls) was added to powdered N-bromosuccinimide (5.5 gms) and the mixture was heated under reflux for 2 hours. A thick red-brown oil sepatated. The product was cooled to 0C for 16 hours and filtered, and the filtrate was evaporated almost to dryness. The product was isolated by chromatography on alumina using carbon tetrachloride/l percent methanol as solvent. The product 4-(4-pyridyl), 4-bromo tetrahydropyran (3 grns) was recrystalised from carbon tetrachloride as unstable white tablets characterised by the following data:

l.R.(CCl,)1590,1395,1150,l100,1040,1025,920 780 cm N.M.R. 1-(CCL,) 1.4, 2.65, 6.15, 7.8 (Relative lnsensities 212:4:4).

M.S. M/e 241.0092 (C H BrNO has M/e 241.0102),162.0918,161.

EXAMPLE 34 Aqueous hydrogen peroxide (21 mls of 30 percent solution) was added over 2 hours to a solution of 4-(4pyridyl)-tetrahydropyran (16.0 gms) in acetic acid (18 mls) at 75C. After 20 hours the mixture was heated to 95C and paraformaldehydr (2.0 grns) was added. After 2 hours the solvent was evaporated in vacuo and the residual oil was added to acetic anhydride (60 mls) at 100C. The product was poured onto ice and made slightly alkaline with potassium hydroxide solution. After 6 hours the product was extracted into diethyl ether, and after removal of the solvent, the product was recrystallised from carbon tetrachloride as white blocks mp. 154C characterised by the following spectral data:

l.R. (nujol mull) 3250, 1600, 1380, 1140. 1120, 1080, 1010. 840 and 830 cm.

N.M.R. 1-(CDCl 60) 1.55, 2.55, 6.15, 6.55, 7.88.5 (Relative intensities 2:2:41124).

M.S. M/e 179.0956 (C H NO 179.0946).

EXAMPLES 35 to These examples illustrate the conversion of substituted pyridines into bipyridyls.

The experimental procedure in each example was as follows:

A catalyst bed was prepared from a pelleted form of the catalyst (see below) to the specified depth in a vertical glass reactor tube of internal diameter 1 inch. The tube was fitted with a central thermocouple pocket and contained Raschig rings above the catalyst bed. The Rashig rings did not completely fill the tube. The tube was positioned in a vertical furnace maintained at the appropriate temperature.

The substituted pyridine was dissolved in water or methanol or (Example 72) pyridine and the solution was fed to the top of the reactor tube where it was vaporised on contact with the Raschig rings. The vapours were passed downwardly through the catalyst bed. The vapours were mixed with oxygen, nitrogen or ammonia as indicated in the Table for passage through the catalyst bed, although in a few cases mixing was carried out below the surface of the catalyst bed.

The reactor effluent was condensed and the condensate if liquid (as in the majority of the experiments) was analysed by gas/liquid chromatography using standard techniques. Where the condensate was a solid this was dissolved in methanol and the solution was analysed.

In the Table the catalyst is designated by a reference letter A, B, C or D:

A. One-eighth inch X one-eighth inch pelleted alumina (Actal A) B. activated copper oxide/chromia (l. C.l. 26-3) C. 0.5 percent platinum on 50 percent alumina/50 percent silica-alumina D. a bed of 13 percent alumina-silica and a bed of alumina (Crosfield-Grade 77) In the Table also:

Bipyridyl means 4,4-bipyridyl unless otherwise stated Length is the length of the catalyst bed Temp. is the temperature of the catalyst bed dilution is in terms of gms starting material/mls solvent MeOH is methanol TABLE Gas feeds 4, 4'- Catalyst Liquid feed bipyridyl Air N: NH: (conver- Ex. Cata- Bed length Temp. Time (m1s./ (mls./ (mls./ sion No. Substituted pyridine lyst (ins.) 0.) (mins.) Dilution Solvent min.) min.) min.) percent) 35---.- 3-(4-pyr1dy1)-1, 1-diethoxy-5-d1- A 3 360-420-..- 51 1.3/ MeOH 100 830 57.

methylamino peutane. 36..... 6-(4-pyridy1)-8-dimethy1am1no-3- A 3 350-390.... 100 2.6/50 HzO/MeOH 100 830 72.

oxaoctan-l-ol. (2:1). 37.-... 3-(4-pgrldfhl-5-dlmethylamino A 3 330-360.... 50 4. 5/30 MeOH 100 830 41.

pen an- -0 38..-.- 3-(4pr1dy1)-1,5 bis-dlmethylamino A 3 320-340.-.- 47 2.4/ MeOH 100 830 39.

pen ane. 39-...- 3-(4-pyr1dyD-5-diethylamino A 3 330-363.--- 70 4.7/18 MeOH 100 830 36.

pentan-l-ol. 40----- 3-(4-pridyl)-1,5 bis-diethylamino A 3 320-380...- 60 3.3/30 MeOH 100 830 34.

pen ane. 41..... S-(gi-pyridyD-S,9-d1oxo-undeca-1,10- A 3 375-401.... 66 2.3/25 MeOH 100 830 26.

ene. 42..-.. 3-(4l-pyridyD-1,1-dieth0xy-pentan-5- A 3 340-360.... 3.5/25 MeOH 100 830 24.

o 43 .-do A 3 350-380--.- 45 3.0/25 H2O/M8OH 100 830 39.

44-..- 3-(4t-l13y1r1dyPaglutaraldehydetetra- A a 355390.... 2.66/25 MeO H 10o s30 86.

e y ace :1 45. o A 3 370-390.--- 77 1.85/25 830 70. 46....- 3-(14;; })l 1;r{dy1)-5,5-dieth0xypentane- A 3 360-400.... 52 1.82/25 Me0I *I-- 830 58.

o 47..-.. 3-(1-F3l'ridyly5-hydroxy pentane-l- A 3 380-415.... 75 2.1/25 MeOH 830 19 0 48....- 3-(4-pyr1dyl)-5-diethy1amino A 3 385-410-..- 1.26/25 MBOH 830 64 entane-l-thlol 49.-... 3- 4-pyr1dyl)-pentane l, 5-d1th101 A MeOH 830 8. 50..... 2-(Z-pyridyl)-tetrahydropyran. A MeOH 830 2.2)!-

DY 1dyl13. 500 20. 500 6. 830 15. 300 10. 830 9. 830 11. 830 2, -b1pyrid 110. 58 ..do B 3% 340-380.... 15/75 830 2,43 {pyr- 6J..... 3-(3-pyr1dyl)-pentane-1,5-diol A 4 370-400.... 5/25 830 3.48111 1)!!!- y 60 ..do B 3 370-380..-. 1.95/25 830 3,4811% 1 y 61--..- 3-(4-pyridyl)-pentane-1,5-diol C 411:1 1% 360-380.... 1.8/25 830 ore reactor. 61n1% 360-364.... 50 5/25 830 bore reactor.

bore reactor. 3+3 in 1% 325-375..-. 59 6.4/25 830 16 bore reactor. -..--do 330-370..-- 51 5/25 830 13. 82 5/25 830 26. 11 hrs--- 51.4/260 830 18.

70 8.6/13 H2O 100 500 12. 30 1.8/39 Pyridine.-.. 60 500 5. Gin 1% 360-380..-- 7 hrs--.. 33/125, MeOH 100 100 830 60.

bore re- 1 actor. --.-.do 360-380.-.. 100 10/50 830 67. .do 360-380.-.. 40 25 830 84. ..-..d0 360-380.-.- 42 2. 5/25 830 17. t 3 340-380-.-. 60 5.1/25 830 3. es er. 78..... Ethyl 3-(4-pyridyD-3-[bis (carhcth- A 3 360-380.... 45 10.1/75 830 5.

oxy) methylI-propioratc. 79... l-(2-pyr1dyl)-pentm1e-l,5-d1ol B 3 330-360.... 75 1.2/25 830 2,2'-b1- ggyridyl 80.. 1-(2-pyridyl)-1,5 diacetoxy pentane.. A 3.. 350-380.... 1.0/25 830 2 3131;) 81... 4-(4-pyridyD-4-hydroxy tetrahydro- A 4 360-380.... 0.4/50 830 10 pyran. 82"... 4-(4-pyr1'dyD-4-bromo tetrahydro- A 4% 370-380.... 1.2/25 830 5 pyran. 83.. 4-(4-pyr1dyD-piperidine A 3 340-405...- 2.08/25 MeOH 100 830 80. 84.- 2-(3-pyridyD-piperidine (Ana- A 3 337-401...- 1.9/25 HzO/MeOH 100 830 2,3'-

basine). (1:1). pyridyl 85-- 4,4-bipiperidyl3-(4-pyridyD-5-di- A 3 370-415.... 30 1.7/18 MeOH 400 15.

ethylamino-pentan-l-ol.

' 1n the above Table the product listed is the major reaction product. However, in many examples other products were identified as follows:

Example No. Other Products 37 4-(4-pyridylJ-tetrahydropyran 19%) N'methyl4-(4-pyridyl) piperidine 38 N-methyl-4-(4-pyridyl) piperidine 39 4-( 4-pyridyl )-tetrahydropyran N-ethyl-4-( 4-pyridyl) piperidinc 40 N-ethyl-4-(4-pyridyl) piperidine 41. 46. 47, 48. 49, 61 4-(4-pyridyl)-tetrahydropyran to 76 57, 58 4-(2-pyridyl)-tetrahydropyran 59, 60 4-(3-pyridy1)-tetrahdropyran 3'-methyl-3,4'-bipyridyl 84 2'- or 3-methyl-2,3-bipyridyl -methyl-2,3-bipyridyl 85 4-(4-pyridyl)-piperidine The majority of the products (including those referred to as other products) in Examples 35 to 85 were identified by comparison with authentic reference compounds. Those which could not be so identified were subjected to fractional distillation or to gas/liquid chromatographic analysis and their spectral data is given below:

N-ethyl 4(4-pyridyl)-piperidine 1.R.vmax (CCL) 3000, 2800, 2780, 1600,, 1440, 1400, 1370 and 1130 cm.

N.M.R. [(CD CO] 1.5, 2.85, 7.1, 7.6-8.4, 8.98 (Relative intensities 2:2: 1 :3).

M.S. M/e 190.1469 (C H N 190.1470).

has M/e 3 ,4 '-Bipyridyl 3-Methyl 3,4-Bipyridyl 1.R. umax (liquid film) 3050, 2950, 1600, 1530, 1450, 1440, 1400, 1020, 835, 820, 805, 750, 740 and 720 cm.

N.M.R. 1-(CC1 1.4-l., 2.45, 2.7, 2.95, 7.72 (Relative intensities 4:111:113).

M.S. M/e 170.0843 (C H N 170.0843).

A Methyl-2,3'-bipyridyl (either 2'- or 3-methyl-2,3 'bipyridyl-characterization incomplete) has M/&

LR. vmax (liquid film) 3020, 1585, 1575, 1405, 1010, 790, 770, 760, 710 cm.

M.S. 170.0833 (C H N has M/e 170.0843).

5-Methyl-2,3'-bipyridyl LR. vmax (nujol mull) 1575, 1420, 1030, 1020, 840, 810, 775, 760 and 710 cml.

N.M.R. 1' (CCl 0.75, 1.4, 1.6, 2.28, 2.42, 2.62, 7.6

has M/e lected from the group consisting of 4,4'-bipyridyls. 3,4-bipyridyls and 2.4-bipyridyls which comprises re acting the corresponding substituted pyridine'with ammonia in the vapour phase at a temperature in the range of 250C to 450C and in the presence of a refractory oxide catalyst, the substituted pyridine being a substituted pyridine wherein the. substituent is a group of the structural formula C(R) (R,) (R wherein R represents a hydrogen atom, and R and R each represents Cl-1 .CH (XR or -CH .CH(XR wherein X represents an atom of sulphur or oxygen and R, represents a hydrogen atom, a lower alkyl, or vinyl.

2. A process as claimed in claim 1, wherein R, is hydrogen or ethyl, and the reaction is carried out in the presence of a catalyst selected from the group consisting of alumina, silica, silica-alumina, magnesia, chromia, and mixtures thereof.

3. A process as claimed in claim 2 wherein said catalyst includes platinum or palladium.

4. A process as claimed in claim 1 wherein the reaction is carried out in the presence of molecular oxygen.

5. A process as claimed in claim 1 wherein the temperature is from 350to 450C.

6. A process as claimed in claim 1 wherein the reac tion is carried out in the absence of oxygen and in which the reaction product is subsequently oxidized to the bipyridyl with molecular oxygen.

7. A process as claimed in claim 1 wherein the reaction is carried out in the presence of molecular oxygen in the form of oxygen gas.

8. A process as claimed in claim 7 wherein the oxygen gas is added in the form of air.

9. A process as claimed in claim 1 wherein the substituted pyridine is obtained in the vapour phase by vaporization of a solution of the derivative.

10. A process as claimed in claim 9 wherein the sol vent is water or methanol.

11. A process as claimed in claim 1 wherein R and R2 are 0r 

1. A PROCESS FOR THE MANUFACTURE OF A DIPYRIDYL SELECTED FROM THE GROUP CONSISTING OF 4,4''-DIPYRIDYLS, 3,4''-DIPYRIDYLS AND 2,4''-DIPYRIDYLS WHICH COMPRISES REACTING THE CORRESPONDING SUBSTITUTED PYRIDINE WITH AMMONIA IN THE VAPOR PHASE AT A TEMPERATURE IN THE RANGE OF 250*C RO 450*C AND IN THE PRESENCE OF A REFACTORY OXIDE CATALYST, THE SUBSTITUTED PYRIDINE BEING A SUBSTITUTED PYRIDINE WHEREIN THE SUBSTITUTED PYRIGROUP OF THE STRUCTURAL FORMULA -C(R) (R1) (R2) WHEREIN R REPRESENTS A HYDROGEN ATOM, AND R1 AND R2 EACH REPRESENTS -CH2 CH2(XR4) OR -CH2CH(XR4)2WHEREIN X REPRESENTS AN ATOM OF SULPHUR OR OXYGEN AND R4 REPRESENTS A HYDROGEN ATOM, A LOWER ALKYL, OR VINYL.
 2. A process as claimed in claim 1, wherein R4 is hydrogen or ethyl, and the reaction is carried out in the presence of a catalyst selected from the group consisting of alumina, silica, silica-alumina, magnesia, chromia, and mixtures thereof.
 3. A process as claimed in claim 2 wherein said catalyst includes platinum or palladium.
 4. A process as claimed in claim 1 wherein the reaction is carried out in the presence of molecular oxygen.
 5. A process as claimed in claim 1 wherein the temperature is from 350*to 450*C.
 6. A process as claimed in claim 1 wherein the reaction is carried out in the absence of oxygen and in which the reaction product is subsequently oxidized to the bipyridyl with molecular oxygen.
 7. A process as claimed in claim 1 wherein the reaction is carried out in the presence of molecular oxygen in the form of oxygen gas.
 8. A process as claimed in claim 7 wherein the oxygen gas is added in the form of air.
 9. A process as claimed in claim 1 wherein the substituted pyridine is obtained in the vapour phase by vaporization of a solution of the derivative.
 10. A process as claimed in claim 9 wherein the solvent is water or methanol.
 11. A process as claimed in claim 1 wherein R1 and R2 are -CH2CH2OH or -CH2CH2SH. 